Disease‐modifying therapies and T1 hypointense lesions in patients with multiple sclerosis: A systematic review and meta‐analysis

Abstract Background Previous research has shown that cerebral T1 hypointense lesions are positively correlated with the disability of multiple sclerosis (MS) patients. Hence, they could be used as an objective marker for evaluating the progression of the disease. Up to this date, there has not been a systematic evaluation of the effects of disease‐modifying therapies (DMTs) on this prognostic marker. Objectives To evaluate the effects of FDA‐approved DMTs on the numbers and volume of T1 hypointense lesions in adult patients with MS. Methods We included studies with the mentioned desired outcomes. In March 2021, we searched MEDLINE (Ovid), Embase, and CENTRAL to find relevant studies. All included studies were assessed for the risk of bias using the RoB‐2 tool. Extracted data were analyzed using a random‐effects model. Certainty of evidence was assessed using GRADE. Results Thirteen studies with 7484 participants were included. Meta‐analysis revealed the mean difference between the intervention and comparator groups for the number of lesions was −1.3 (95% CI: −2.1, −0.5) and for the mean volume of lesions was −363.1 (95% CI: −611.6, −114.6). Certainty of evidence was judged to be moderate. Heterogeneity was considerable. Discussion DMTs reduce the number and volume of T1 hypointense lesions. Although, these findings must be interpreted cautiously due to the high values of heterogeneity.

1.1 Was the allocation sequence random?
The use of randomization methods is clearly stated in the study.
1.2 Was the allocation sequence concealed until participants were enrolled and assigned to interventions?
Allocation sequence concealment is clearly stated.
1.3 Did baseline differences between intervention groups suggest a problem with the randomization process?
Age, sex, and ethnicityare not significantly different between the groups.
Domain 1b: Risk of bias arising from the timing of identification or recruitment of participants in a cluster-randomized trial (for Cluster randomized controlled trials only) 1b.1 Were all the individual participants identified and recruited (if appropriate) before the randomization of clusters?
All participants were identified and recruited before the clusters were randomized, or individual participants were not recruited at all but all were identified before randomization.
1b.2 If N/PN/NI to 1b.1: Is it likely that the selection of individual participants was affected by knowledge of the intervention assigned to the cluster?
Recruiting individuals were aware of cluster allocation before recruitment, or some participants were aware of cluster allocation before their recruitment, or those identifying potential participants (when recruitment is to take place subsequently) are aware of cluster allocation, or those identifying actual participants (when there is no subsequent recruitment) are aware of cluster allocation.

1b.3
Were there baseline imbalances that suggest differential identification or recruitment of individual participants between intervention groups? Imbalances that are compatible with a chance should not be interpreted as suggesting differential identification or recruitment of participants.

Domain S: Risk of bias arising from period and carryover effects (for Cross-over randomized controlled trials only)
S.1 Was the number of participants allocated to each of the two sequences equal or nearly equal?
No: We only include the results from the first phase of a cross-over trial.
S.2 If N/PN/NI to S.1: Were period effects accounted for in the analysis?
No: We only include the results from the first phase of a cross-over trial.
S.3 Was there sufficient time for any carryover effects to have disappeared before outcome assessment in the second period?
No: We only include the results from the first phase of a cross-over trial.

Domain 2: Risk of bias due to deviations from the intended interventions (effect of assignment to intervention)
2.1. Were participants aware of their assigned intervention during the trial?
The allocation sequence was concealed for patients.
2.2. Were carers and people delivering the interventions aware of participants' assigned interventions during the trial?
The allocation sequence was concealed for care providers.
2.3. If Y/PY/NI to 2.1 or 2.2: Were there deviations from the intended intervention that arose because of the trial context?
There is evidence or strong reason to believe that the trial context led to failure to implement the protocol interventions or to implementation of interventions not allowed by the protocol. Deviations are not balanced between the intervention groups.
2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention?
Intention-to-treat (ITT) analyses and modified intention-to-treat (mITT) analyses are appropriate. 2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyze participants in the group to which they were randomized?
The number of participants who were analyzed in the wrong intervention group, or excluded from the analysis, was sufficient that there could have been a substantial impact on the result. Non-adherence includes imperfect compliance with a sustained intervention, cessation of intervention, crossovers to the comparator intervention, and switches to another active intervention.
2.6. If N/PN/NI to 2.3, or Y/PY/NI to 2.4 or 2.5: Was an appropriate analysis used to estimate the effect of adhering to the intervention?
Appropriate methods include (1) instrumental variable analyses to estimate the effect of receiving the assigned intervention in trials in which a single intervention, administered only at baseline and with all-or-nothing adherence, is compared with standard care; and (2) inverse probability weighting to adjust for censoring of participants who cease adherence to their assigned intervention, in trials of sustained treatment strategies.
Domain 3: Risk of bias due to missing outcome data 3.1 Were data for this outcome available for all, or nearly all, participants randomized?
Availability of data from 95% of the participants will be considered sufficient (imputed data will be regarded as missing data).
3.2 If N/PN/NI to 3.1: Is there evidence that the result was not biased by missing outcome data?
Analysis methods corrected for bias, or sensitivity analyses were performed showing that results are little changed under a range of plausible assumptions about the relationship between missingness in the outcome and its true value.
3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value?
Loss to follow-up, or withdrawal from the study, could be related to participants' health status.
3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value?
There are differences between intervention groups in the proportions of missing outcome data. Reported reasons for missing outcome data differ between the intervention groups; or reported reasons for missing outcome data to provide evidence that missingness in the outcome depends on its true value.